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Osteosarcoma/Bone Fibrous Histiocytoma Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of osteosarcoma and malignant fibrous histiocytoma of bone. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

Incidence.

Prognostic factors.

Cellular classification.

Stage information.

Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

General Information

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, an orthopedic surgeon experienced in bone tumors, a pathologist, radiation oncologists, pediatric oncologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Osteosarcoma occurs predominantly in adolescents and young adults. It accounts for approximately 5% of childhood tumors. In children and adolescents, more than 50% of these tumors arise from the bones around the knee. Osteosarcoma can rarely be observed in soft tissue or visceral organs. There appears to be no difference in presenting symptoms, tumor location, and outcome for younger patients (<10 years) compared with adolescents.[2,3] Two trials conducted in the 1980s were designed to address the natural history of surgically treated localized, resectable osteosarcoma of the extremity. The outcome of patients in these trials who were treated with surgical removal of the primary tumor recapitulated the historical experience before 1970; more than half of these patients developed metastases within 6 months of diagnosis, and overall, approximately 90% developed recurrent disease within 2 years of diagnosis.[4] Overall survival for patients treated with surgery alone was statistically inferior.[5] The natural history of osteosarcoma has not changed over time, and fewer than 20% of patients with localized resectable primary tumors treated with surgery alone can be expected to survive free of relapse.[4,6,7]

References:

1.

Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.

Prognostic Factors

Pretreatment factors that influence outcome include site and size of the primary tumor, and presence or absence of clinically detectable metastatic disease. After administration of preoperative chemotherapy, surgical resectability and the degree of tumor necrosis influence outcome. In general, prognostic factors in osteosarcoma have not been helpful in identifying patients who might benefit from treatment intensification or who might require less therapy while maintaining an excellent outcome.

Primary Site

The site of the primary tumor is a significant prognostic factor for patients with localized disease. Among extremity tumors, distal sites have a more favorable prognosis than proximal sites. Axial skeleton primary tumors are associated with the greatest risk of progression and death, primarily related to the inability to achieve a complete surgical resection. Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas; survival rates for patients with pelvic primary tumors are 20% to 47%.[1,2] For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure.[3,4,5] Despite a relatively high rate of inferior necrosis following neoadjuvant chemotherapy, fewer patients with craniofacial primaries develop systemic metastases than do patients with osteosarcoma originating in the extremities.[6,7,8] This low rate of metastasis may be related to the relatively smaller size and higher incidence of lower grade tumors in osteosarcoma of the head and neck. There is a better prognosis for patients who have osteosarcoma of the head and neck than for those who have appendicular lesions when treated with surgery alone. While small series have not shown a benefit from adjuvant chemotherapy for patients with osteosarcoma of the head and neck, one meta-analysis concluded that systemic chemotherapy improves the prognosis for these patients. Another large meta-analysis detected no benefit from chemotherapy for patients with osteosarcoma of the head and neck, but suggested that the incorporation of chemotherapy into treatment of patients with high-grade tumors may improve survival. A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy.[5,9] Radiation-associated craniofacial osteosarcomas are generally high-grade lesions, usually fibroblastic, which tend to recur locally and have a high rate of metastasis.[10]

Osteosarcoma in extraskeletal sites is rare in children and young adults. With current combined-modality therapy, the outcome for patients with extraskeletal osteosarcoma appears to be similar to that for patients with primary tumors of bone.[11]

Tumor Size

Larger tumors have a worse prognosis than smaller tumors. Tumor size has been assessed by the longest single dimension, by the cross-sectional area, or by an estimate of tumor volume; all have correlated with outcome. Serum lactate dehydrogenase (LDH), which also correlates with outcome, is a likely surrogate for tumor volume.

Presence of Clinically Detectable Metastatic Disease

Patients with localized disease have a much better prognosis than those with overt metastatic disease. As many as 20% of patients will have radiographically detectable metastases at diagnosis, with the lung being the most common site.[12] The prognosis for patients with metastatic disease appears to be determined largely by the site(s), the number of metastases, and the surgical resectability of the metastatic disease.[13,14] Patients who have complete surgical ablation of the primary and metastatic tumor (when confined to the lung) following chemotherapy may attain long-term survival, though overall event-free survival remains about 20% to 30% for patients with metastatic disease at diagnosis.[13,14,15,16] Prognosis appears more favorable for patients with fewer pulmonary nodules and for those with unilateral rather than bilateral pulmonary metastases;[13] not all patients with suspected pulmonary metastases at diagnosis have osteosarcoma confirmed at the time of lung resection. In one large series, approximately 25% of patients had exclusively benign lesions removed at the time of surgery.[14] The degree of necrosis in the primary tumor after induction chemotherapy remains prognostic in metastatic osteosarcoma.[17] Patients with skip metastases (at least two discontinuous lesions in the same bone) have been reported to have inferior prognoses.[18] Analysis of the German Cooperative Osteosarcoma Study experience, however, suggests that skip lesions in the same bone do not confer an inferior prognosis if they are included in planned surgical resection. Skip lesions across a joint have a worse prognosis.[19] Patients with multifocal osteosarcoma (defined as multiple bone lesions without a clear primary tumor) have an extremely poor prognosis.[20]

Adequacy of Tumor Resection

Resectability of the tumor is a critical prognostic feature because osteosarcoma is relatively resistant to radiation therapy. Complete resection of the primary tumor and any skip lesions with adequate margins is generally considered essential for cure. For patients with axial skeletal primaries who either do not have surgery for their primary tumor or who have surgery resulting in positive margins, radiation therapy may improve survival.[1,21]

Necrosis Following Induction or Neoadjuvant Chemotherapy

Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy prior to definitive resection of the primary tumor (or resection of sites of metastases for patients with metastatic disease). The pathologist assesses necrosis in the resected tumor. Patients with at least 90% [22] necrosis in the primary tumor after induction chemotherapy have a better prognosis than those with less necrosis.[22] Patients with less necrosis (<90%) in the primary tumor following initial chemotherapy have a higher rate of recurrence within the first 2 years compared with patients with a more favorable amount of necrosis (=90%).[23] Imaging modalities such as dynamic magnetic resonance imaging or positron emission tomography (PET) scanning are under investigation as noninvasive methods to assess response.[24,25] Less necrosis should not be interpreted to mean that chemotherapy has been ineffective; cure rates for patients with little or no necrosis following induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy.

Additional Prognostic Factors

Patients with osteosarcoma as a second malignant neoplasm including those tumors arising in a radiation field, share the same prognosis as patients with de novo osteosarcoma if they are treated aggressively with complete surgical resection and multiagent chemotherapy.[26,27,28,29] There have been numerous other identified prognostic features for patients with conventional localized high-grade osteosarcoma. These factors include the age of the patient, LDH level, alkaline phosphatase level, and histologic subtype.[22,30,31,32,33] A number of potential prognostic factors have been identified but have not been tested in large numbers of patients. These include the expression of HER2/c-erbB-2 (there are conflicting data concerning the prognostic significance of this human epidermal growth factor);[34,35,36] tumor cell ploidy; specific chromosomal gains or losses;[37] loss of heterozygosity (LOH) of the RB gene;[38,39] LOH of the p53 locus;[40] and increased expression of p-glycoprotein.[41,42] A prospective analysis of p-glycoprotein expression determined by immunohistochemistry failed to identify prognostic significance for newly diagnosed patients with osteosarcoma, although earlier studies suggested that overexpression of p-glycoprotein predicted for poor outcome.[43]

Syndromes Associated with Osteosarcoma

Rothmund-Thomson syndrome

Patients with Rothmund-Thomson syndrome and RECQL4 gene mutations have an increased risk of developing osteosarcoma compared with the general population. They also tend to develop osteogenic sarcoma at a younger age.[44] There is no adverse prognostic significance for osteosarcoma in conjunction with Rothmund-Thomson syndrome.

Bacci G, Mercuri M, Longhi A, et al.: Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution. Eur J Cancer 41 (14): 2079-85, 2005.

Cellular Classification

Osteosarcoma is a malignant tumor that is characterized by the direct formation of bone or osteoid tissue by the tumor cells. The World Health Organization's histologic classification [1] of bone tumors separates the osteosarcomas into central (medullary) and surface (peripheral) [2,3] tumors and recognizes a number of subtypes within each group.

The most common pathologic subtype is conventional central osteosarcoma, which is characterized by areas of necrosis, atypical mitoses, and malignant osteoid tissue and/or cartilage. The other subtypes are much less common, each occurring at a frequency of less than 5%. Telangiectatic osteosarcoma may be confused radiographically with an aneurysmal bone cyst or giant cell tumor. This variant should be approached as a conventional osteosarcoma.[4,5] Recognition of intraosseous well-differentiated osteosarcoma and parosteal osteosarcoma is important because these are associated with the most favorable prognosis and can be treated successfully with radical excision of the primary tumor alone.[6,12] Periosteal osteosarcoma has a generally good prognosis [8] and treatment is guided by histologic grade.[9,12]

Malignant fibrous histiocytoma (MFH) of bone is treated according to osteosarcoma treatment protocols. MFH should be distinguished from angiomatoid fibrous histiocytoma, a low-grade tumor that is usually noninvasive, small, and associated with an excellent outcome with surgery alone.[13] One study suggests similar event-free survival rates for MFH and osteosarcoma.[14]

Extraosseous osteosarcoma is a malignant mesenchymal neoplasm without direct attachment to the skeletal system. Previously, treatment for extraosseous osteosarcoma followed soft tissue sarcoma guidelines,[15] though a retrospective analysis of the German Cooperative Osteosarcoma Study identified a favorable outcome for extraosseous osteosarcoma treated with surgery and conventional osteosarcoma therapy.[16]

Staging and Site Information

The Enneking staging system for musculoskeletal neoplasms is based on grade, site, and presence of metastases.[1] All conventional osteosarcomas are high grade; site is graded as intracompartmental or extracompartmental. To be intracompartmental, an osteosarcoma must be confined within the periosteum; such lesions are IIA in the Enneking system. The great majority of osteosarcomas extend beyond the periosteum, which makes them IIB. The presence of clinically detectable metastases is graded as stage III in this system. For practical purposes, there are essentially two classes of patients: those who present without clinically detectable metastatic disease (localized osteosarcoma) and those who present with clinically detectable metastatic disease (metastatic osteosarcoma).

Localized Osteosarcoma

Localized tumors are limited to the bone of origin. Patients with skip lesions confined to the bone which includes the primary tumor should be considered to have localized disease if the skip lesions can be included in the planned surgical resection.[2] Approximately one-half of the tumors arise in the femur; of these, 80% are in the distal femur. Other primary sites in descending order of frequency are the proximal tibia, proximal humerus, pelvis, jaw, fibula, and ribs.[3] Compared with osteosarcoma of the appendicular skeleton, osteosarcoma of the head and neck is more likely to be low grade [4] and to arise in older patients. A retrospective analysis identified a trend toward better survival in patients with osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy.[5]

Metastatic Osteosarcoma

Radiologic evidence of metastatic tumor deposits in the lungs, other bones, or other distant sites is found in approximately 20% of patients at diagnosis, with 85% to 90% of metastatic disease presenting in the lungs. The second most common site of metastasis is another bone.[6] Metastasis to other bones may be solitary or multiple. The syndrome of multifocal osteosarcoma refers to a presentation with multiple foci of osteosarcoma without a clear primary tumor, often with symmetrical metaphyseal involvement. Multifocal osteosarcoma has an extremely grave prognosis.[3]

Treatment Option Overview

Successful treatment generally requires the combination of effective systemic chemotherapy and complete resection of all clinically detectable disease. Protective weight bearing is recommended for patients with tumors of weight-bearing bones to prevent pathological fractures that could preclude limb-preserving surgery.

Randomized clinical trials have established that both neoadjuvant and adjuvant chemotherapy are effective in preventing relapse in patients with clinically nonmetastatic tumors.[1,2] The Pediatric Oncology Group conducted a study in which patients were randomized either to immediate amputation or amputation after neoadjuvant therapy. A large percentage of patients declined randomization and the study was terminated without approaching the stated accrual goals. In the small number of patients treated, there was no difference in outcome for those who received preoperative versus postoperative chemotherapy.[3] It is imperative that patients with proven or suspected osteosarcoma have an initial evaluation by an orthopedic oncologist familiar with the surgical management of this disease. This evaluation, which includes imaging studies, should be done prior to the initial biopsy, since an inappropriately performed biopsy may jeopardize a limb-sparing procedure.

Localized Osteosarcoma / Malignant Fibrous Histiocytoma of Bone

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Complete surgical resection is crucial for patients with localized osteosarcoma; however, at least 80% of patients treated with surgery alone will develop metastatic disease.[1] Randomized clinical trials have established that adjuvant chemotherapy is effective in preventing relapse or recurrence in patients with localized resectable primary tumors.[1,2] Patients with malignant fibrous histiocytoma (MFH) of bone are treated according to osteosarcoma treatment protocols, and the outcome for patients with resectable MFH is similar to the outcome for patients with osteosarcoma.[3] As with osteosarcoma, patients with a favorable necrosis had a longer survival than those with an inferior necrosis.[4] MFH of bone is seen more commonly in older adults. Many patients with MFH will need preoperative chemotherapy to achieve a wide local excision.[5]

Biopsy

While a needle biopsy can often make the diagnosis of osteosarcoma, participation in clinical trials may require collection of material for biologic studies that can only be obtained via an open biopsy or multiple needle biopsies. If limb sparing (removal of the malignant bone tumor without amputation and replacement of bones or joints with allografts or prosthetic devices) is contemplated, the biopsy should be performed by the surgeon who will do the definitive operation, since incision placement is crucial.

Surgical Removal of Primary Tumor

Surgical resection of the primary tumor with adequate margins is an essential component of the curative strategy for patients with localized osteosarcoma. The type of surgery required for complete ablation of the primary tumor depends on a number of factors that must be evaluated on a case-by-case basis.[6] In general, more than 80% of patients with extremity osteosarcoma can be treated by a limb sparing procedure and do not require amputation.[7] Limb sparing procedures should be planned only when the preoperative staging indicates that it would be possible to achieve wide surgical margins. Reconstruction after surgery can be accomplished with many options including metallic endoprosthesis, allograft, vascularized autologous bone graft, and rotationplasty. The choice of optimal surgical reconstruction involves many factors, including the site and size of the primary tumor, the ability to preserve the neurovascular supply of the distal extremity, the age of the patient and potential for additional growth, and the needs and desires of the patient and family for specific function, such as sports participation. If a complicated reconstruction delays or prohibits the resumption of systemic chemotherapy, limb preservation may endanger the chance for cure. For some patients, amputation remains the optimal choice for management of the primary tumor. A pathologic fracture noted at diagnosis or during preoperative chemotherapy does not preclude limb-salvage surgery if wide surgical margins can be achieved.[8] In one series, patients presenting with a pathologic fracture at diagnosis had similar outcomes to those without pathologic fractures at diagnosis, while in a second series, pathologic fracture at diagnosis was associated with a worse overall outcome.[9,10] If the pathologic examination of the surgical specimen shows inadequate margins, an immediate amputation should be considered, especially if the histologic necrosis following preoperative chemotherapy was poor.[11] In one study, patients undergoing limb-salvage procedures who had poor histologic response and close surgical margins had a high rate of local recurrence.[12]

Not surprisingly, patients who undergo amputation have lower local recurrence rates than patients who undergo limb salvage procedures. Patients with tumors of the femur have a higher local recurrence rate than patients with primary tumors of the tibia/fibula. Rotationplasty and other limb salvage procedures have been evaluated for both their functional outcome and their effect on survival. There is no difference in overall survival (OS) between patients initially treated by amputation and those treated with a limb sparing procedure. While limb sparing resection is the current practice for local control at most pediatric institutions, there are few data to indicate that limb-salvage of the lower limb is substantially superior to amputation with regard to patient quality of life.

If complete surgical resection is not feasible or if surgical margins are inadequate, radiation therapy may improve the local control rate.[13,14]

Chemotherapy

Almost all patients receive intravenous preoperative chemotherapy as initial treatment. Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin.[15,16,17,18,19,20,21,22,23,24] Although most patients with osteosarcoma receive high-dose methotrexate as part of initial therapy, patients treated with doxorubicin, cisplatin, cyclophosphamide, and vincristine (without high-dose methotrexate) have a similar outcome to that of patients receiving high-dose methotrexate.[25]

In certain trials, extent of tumor necrosis is used to determine postoperative chemotherapy. In general, if tumor necrosis exceeds 90%, the preoperative chemotherapy regimen is continued. If tumor necrosis is less than 90%, some groups have incorporated drugs not previously utilized in the preoperative therapy. This approach is based on early reports from Memorial Sloan-Kettering Cancer Center (MMSKC) which suggested that adding cisplatin to postoperative chemotherapy improved the outcome for patients with less than 90% tumor necrosis. With longer followup, the outcome for patients with less than 90% tumor necrosis treated at MSKCC was the same whether they did or did not receive cisplatin in the postoperative phase of treatment. Subsequent trials performed by other groups have failed to demonstrate improved event-free survival (EFS) when drugs not included in the preoperative regimen were added to postoperative therapy.[17,26]

The Children's Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection. The addition of ifosfamide did not improve outcome. The addition of MTP-PE produced improvement in EFS which did not meet the conventional test for statistical significance (p = .08), and a significant improvement in OS (78% vs. 70%; p = .03).[27][Level of evidence: 1iiA] There has been speculation regarding the potential contribution of postrelapse treatment, although there was no differences in the postrelapse surgical approaches in the relapsed patients. The appropriate role of MTP in the treatment of osteosarcoma remains under discussion.

Treatment Options Under Clinical Evaluation

The COG, in collaboration with several European groups, has opened a trial in which all patients receive preoperative therapy with doxorubicin, cisplatin, and high-dose methotrexate. Patients are then divided into the following two strata on the basis of histologic necrosis in the resected primary tumor:

FAVORABLE HISTOLOGIC RESPONSE (<10% VIABLE TUMOR): COG-AOST0331: In this trial, all patients receive postoperative therapy with the same drugs as those given preoperatively. Patients will be randomly assigned to receive additional therapy with pegylated interferon alpha-2b.[28]

STANDARD HISTOLOGIC RESPONSE (10%–100% VIABLE TUMOR):COG-AOST0331: In this trial, patients will be randomly assigned to receive postoperative chemotherapy with the same drugs as those given preoperatively plus or minus additional courses of ifosfamide/etoposide.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with localized osteosarcoma and localized childhood malignant fibrous histiocytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Osteosarcoma with Metastatic Disease at Diagnosis

Approximately 20% to 25% of patients with osteogenic sarcoma present with clinically detectable metastatic disease. The lung is the most common site of initial metastatic disease.[1] For patients with metastatic disease at initial presentation, roughly 20% will remain continuously free of disease, and roughly 30% will survive 5 years from diagnosis.[2] Patients with metastases limited to the lungs have a better outcome than patients with metastases to other sites or to the lungs combined with other sites.[2,3] The chemotherapeutic agents used include high-dose methotrexate, doxorubicin, cisplatin, high-dose ifosfamide, etoposide, and in some reports, carboplatin or cyclophosphamide. High-dose ifosfamide (17.5 grams per course) in combination with etoposide produced a complete (10%) or partial (49%) response in patients with newly diagnosed metastatic osteosarcoma.[4]

Lung Metastases Only

Patients with metastatic lung lesions as the sole site of metastatic disease should have the lung lesions resected if at all possible. Generally, this is done following administration of preoperative chemotherapy. In approximately 10% of patients, all lung lesions disappear following preoperative chemotherapy.[3] Complete resection of pulmonary metastatic disease can be achieved in a high percentage of patients with residual lung nodules following preoperative chemotherapy. The cure rate is essentially zero without complete resection of residual pulmonary metastatic lesions.

For patients who present with primary osteosarcoma and metastases limited to the lungs and who achieve complete surgical remission, 5-year event-free survival (EFS) is approximately 20% to 25%. Multiple metastatic nodules confer a worse prognosis than one or two nodules, and bilateral lung involvement is worse than unilateral.[2] Patients with fewer than three nodules confined to one lung may achieve a 5-year EFS of approximately 40% to 50%.

Bone Only or Bone with Lung Metastasis

The second most common site of metastasis is another bone that is distant from the primary tumor. Patients with metastasis to other bones distant from the primary tumor experience roughly 10% EFS and overall survival.[2] In the Italian experience, of the patients who presented with primary extremity tumors and synchronous metastasis to other bones, only three patients remained continuously disease-free 5 years later.[5] Patients who have transarticular skip lesions have a poor prognosis.[6]

Multifocal osteosarcoma is different from osteosarcoma which presents with a clearly delineated primary lesion and limited bone metastasis. Multifocal osteosarcoma classically presents with symmetrical, metaphyseal lesions, and it may be difficult to decide which is the primary lesion. Patients with multifocal bone disease at presentation have an extremely poor prognosis. No patient with synchronous multifocal osteosarcoma has ever been reported to be cured, but systemic chemotherapy and aggressive surgical resection may achieve significant prolongation of life.[7,8]

When the usual treatment course of preoperative chemotherapy followed by surgical ablation of the primary tumor and resection of all overt metastatic disease (usually lungs) followed by postoperative combination chemotherapy cannot be used, an alternative treatment approach may be used. This alternative treatment approach begins with surgery for the primary tumor, followed by chemotherapy and then surgical resection of metastatic disease (usually lungs). This alternative approach may be appropriate in patients with intractable pain, pathologic fracture, or uncontrolled infection of the tumor when initiation of chemotherapy could create risk of sepsis.

Treatment Options Under Clinical Evaluation

The Children's Oncology Group, in collaboration with several European groups, has opened a trial in which all patients with sites of metastatic disease amenable to surgical resection receive preoperative therapy with doxorubicin, cisplatin, and high-dose methotrexate. Patients are then divided into the following two strata on the basis of necrosis observed in the resected primary tumor:

FAVORABLE HISTOLOGIC RESPONSE (<10% VIABLE TUMOR): COG-AOST0331: In this trial, all patients receive postoperative therapy with the same drugs as those given preoperatively. Patients will be randomly assigned to receive additional therapy with pegylated interferon alpha-2b.[9]

STANDARD HISTOLOGIC RESPONSE (10%–100% VIABLE TUMOR): COG-AOST0331: In this trial, patients will be randomly assigned to receive postoperative chemotherapy with the same drugs as those given preoperatively plus or minus additional courses of ifosfamide/etoposide.

Malignant Fibrous Histiocytoma of Bone

The treatment for malignant fibrous histiocytoma (MFH) of bone with metastasis at initial presentation is the same as the treatment for osteosarcoma with metastasis. Patients with unresectable or metastatic MFH have a very poor outcome.[10]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with metastatic osteosarcoma and metastatic childhood malignant fibrous histiocytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Recurrent Osteosarcoma

Approximately 50% of relapses occur within 18 months of therapy termination and only 5% of recurrences develop beyond 5 years.[1,2,3,4] In two large series, the incidence of recurrence by site was as follows: lung only (65%–80%), bone only (8%–10%), local recurrence only (4%–7%), and combined relapse (10%–15%).[4,5] Patients with recurrent osteosarcoma should be assessed for surgical resectability, as they may sometimes be cured with aggressive surgical resection with or without chemotherapy.[6,5,7,8,9,10] The ability to achieve a complete resection of recurrent disease is the most important prognostic factor at first relapse, with a 5-year survival rate of 20% to 45% following complete resection of metastatic pulmonary tumors and a 20% survival rate following complete resection of metastases at other sites.[4,5,10,11]

The role of systemic chemotherapy for the treatment of patients with recurrent osteosarcoma is not well defined. The selection of further systemic treatment depends on many factors, including the site of recurrence, the patient's previous primary treatment, and individual patient considerations. Ifosfamide alone with mesna uroprotection, or in combination with etoposide, has shown activity in as many as one-third of patients with recurrent osteosarcoma who have not previously received this drug.[12,13,14,15] Cyclophosphamide and etoposide have activity in recurrent osteosarcoma [16] as does the combination of gemcitabine and docetaxel.[17] Peripheral blood stem cell transplant utilizing high-dose chemotherapy does not appear to improve outcome. High-dose samarium-153-EDTMP coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases.[18,19,20,21]

Lung Only Recurrence

Repeated resections of pulmonary recurrences can lead to extended disease control and possibly cure for some patients.[11,22] Survival for patients with unresectable metastatic disease is less than 5%.[5,23] Five-year event free survical (EFS) for patients who have complete surgical resection of all pulmonary metastases ranges from 20% to 45%.[4,5,10,11] Factors that suggest a better outcome include fewer pulmonary nodules, unilateral pulmonary metastases,[24] or longer intervals between primary tumor resection and metastases.[4,5,25] Resection of metastatic disease followed by observation alone results in low overall survival and disease-free survival. A high percentage of patients with pulmonary nodules identified in only one lung who underwent staged bilateral thoracotomy were found to have palpable nodules in both lungs that were not visualized on a computed tomography scan. This suggests that patients with unilateral nodules may benefit from bilateral exploration.[24]

Bone Metastases Only

Patients with osteosarcoma who develop bone metastases have a poor prognosis. In one large series, the 5-year EFS rate was 11%.[26] Patients with late solitary bone relapse have a 5-year EFS rate of approximately 30%.[26,27,28]

Local Recurrence

The postrelapse outcome of patients who have a local recurrence is worse than that for patients who relapse with metastases alone.[29,30,31]

Two retrospective, single-institution series reported 10% to 40% survival following local recurrence without associated systemic metastasis.[32,33,34,35] The survival for patients with local recurrence and either prior or concurrent systemic metastases is poor.[34] The incidence of local relapse was higher in patients who had a poor pathologic response to chemotherapy in the primary tumor and in patients with inadequate surgical margins.[29,33]

Second Recurrence of Osteosarcoma

The Cooperative Osteosarcoma Study group reported on 249 patients who had a second recurrence of osteosarcoma. The main feature of therapy was repeated surgical resection of recurrent disease. Of these patients, 197 died, 37 are alive in complete remission (24 after a third complete response and 13 after fourth or subsequent complete response). Fifteen patients remain alive who did not achieve surgical remission but follow-up for these patients was extremely short.[36]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent osteosarcoma and recurrent childhood malignant fibrous histiocytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Bacci G, Forni C, Longhi A, et al.: Local recurrence and local control of non-metastatic osteosarcoma of the extremities: a 27-year experience in a single institution. J Surg Oncol 96 (2): 118-23, 2007.

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Changes to This Summary (08 / 14 / 2009)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

PROGNOSTIC FACTORS

Added Syndromes Associated with Osteosarcoma as a new subsection.

TREATMENT OPTION OVERVIEW

Added text to state that the Pediatric Oncology Group conducted a study in which patients were randomized either to immediate amputation or amputation after neoadjuvant therapy, but the study was terminated without approaching the stated accrual goals. In the small number of patients treated, there was no difference in outcome for those who received preoperative versus postoperative chemotherapy (added Goorin et al. as reference 3).

LOCALIZED OSTEOSARCOMA/MALIGNANT FIBROUS HISTIOCYTOMA OF BONE

Added Smeland et al. as reference 26.

RECURRENT OSTEOSARCOMA

Added Second Recurrence of Osteosarcoma as a new subsection.

Added text to state that the Cooperative Osteosarcoma Study group reported on 249 patients with a second recurrence of osteosarcoma treated with repeated surgical resection of recurrent disease. Of these patients, 197 died, 37 are alive in complete remission, and 15 remain alive who did not achieve surgical remission (added Bielack et al. as reference 36).

Added text about three protocols as examples of appropriate clinical trials for patients with metastatic disease.

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ABOUT PDQ

PDQ® - NCI's Comprehensive Cancer Database.

Full description of the NCI PDQ database.

ADDITIONAL PDQ SUMMARIES

PDQ® Cancer Information Summaries: Adult Treatment

Treatment options for adult cancers.

PDQ® Cancer Information Summaries: Pediatric Treatment

Treatment options for childhood cancers.

PDQ® Cancer Information Summaries: Supportive and Palliative Care

Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

Information about complementary and alternative forms of treatment for patients with cancer.

IMPORTANT:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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